The aging of skin may be understood as being influenced by intrinsic factors and extrinsic factors. Intrinsic factors include natural changes to the skin, which are regulated by genetic makeup. Extrinsic factors include exogenous influences such as UV damage, environmental factors, and the like.
Aging of the skin can adversely affect elasticity and strength of the skin through changes in the two main constituents of the dermal extracellular matrix, the fibrous proteins collagen and elastin. For example, elastin is a large fibrous protein formed by the crosslinking of elastin precursor protein molecules (e.g., tropoelastin) into spiral filaments. Collagen, more ubiquitous than elastin, is another fibrous protein that forms the structural network of skin.
Certain agents are known for their beneficial effect of inhibiting the degradation of crosslinked elastin. For example, it is known that matrix metalloproteinases (MMPs), a group of enzymes that are able to break down the macromolecules in the extracellular matrix, play an important role in elastin degradation. A number of plant extracts have been described as inhibitors of various MMPs. For instance, J. L. Lamaison describes the inhibition of elastase (porcine pancreatic elastase) with extracts of plants selected from the rosaceae group and attributes the inhibition to the tannins they contain. Ann. Pharmaceutiques Francaises 1990, 48, 335-340. M. Herrmann et al. disclose that SymMatrix, a hydroalcoholic blackberry leaf extract, exhibits the MMP-1, MMP-2, and MMP-9 inhibitory activity. SOFW Journal (2006), 132(4), 42-46.
In addition, certain natural or synthetic compounds are known for the beneficial effect of promoting the production of elastin precursor and/or promoting the formation of collagen. For example, retinoids up-regulate elastin production in fibroblasts. Liu et al., Am J Physiol. 1993 November; 265(5 Pt 1):L430-437. Retinoids are also known to promote collagen formation.
Furthermore, it has also been noted that certain agents positively influence the cross-linking of tropoelastin. For example, lysyl oxidase serves as a crosslinking enzyme and an element of the scaffold to ensure spatially defined deposition of elastin. Liu et al., Nature Genetics (2004), 36(2), 178-182. Valerie et al. disclose a dill extract that induces the lysyl oxidase (LOXL) gene expression, which is responsible for elastin cross-linking in adults. Experimental Dermatology (2006), 15(8), 574-81. Additionally, currant, cardamon, black radish, box holly, Asea foetida gum, ethyl hexenoate, methyl butyrate, and ethyl decadienoate are disclosed as promoters of LOXL gene expression. GB 2,438,999.
Thus, numerous pathways and agents have been proposed to positively influence elastin and collagen, and skin-properties related thereto. However, the inventors have recognized a need for new agents and combinations of agents that can further positively influence either elastin or collagen, or preferably both.
The inventors have now surprisingly discovered surprising benefits of a particular class of anti-inflammatory compounds, agents that inhibit the cell transcription factor nuclear kappa-B (NFκB). The inventors have found that while NFκB-inhibitors do not themselves necessarily enhance tropoelastin activity, when NFκB-inhibitors are combined with tropoelastin promoters, the resulting combinations exhibit a surprisingly large, unexpected and synergistic boost in tropoelastin promotion efficacy. Even more surprisingly, the inventors have identified certain compounds such as resorcinol derivatives, previously unknown for their inhibitory activity on NFκB, as particularly suitable to dramatically boost the tropoelastin activity of tropoelastin promoters.